Asymmetric aminolysis of aromatic epoxides: A facile catalytic enantioselective synthesis of anti-β-amino alcohols

Article abstract of DOI:10.1021/ol049372t

The first asymmetric aminolysis of trans-aromatic epoxides with anilines is described. The process affords enantioenriched anti-β-amino alcohols in up to 99% ee. The complete regio- and diastereoselectivity observed uses commercially available [Cr(Salen)CI] as a Lewis acid catalyst and in combination with a very simple experimental procedure renders the present reaction a facile and practical tool for the synthesis of chiral nonracemic anti-β-amino alcohols.

Full text of DOI:10.1021/ol049372t

ORGANIC
LETTERS
2
004
Vol. 6, No. 13
173-2176
Asymmetric Aminolysis of Aromatic
Epoxides: A Facile Catalytic
Enantioselective Synthesis of
anti-â-Amino Alcohols
2
Giuseppe Bartoli,* Marcella Bosco, Armando Carlone, Manuela Locatelli,
Massimo Massaccesi, Paolo Melchiorre,* and Letizia Sambri
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna,
V.le Risorgimento 4, 40136 Bologna, Italy
giuseppe.bartoli@unibo.it; pm@ms.fci.unibo.it
Received April 7, 2004
ABSTRACT
The first asymmetric aminolysis of trans-aromatic epoxides with anilines is described. The process affords enantioenriched anti-â-amino
alcohols in up to 99% ee. The complete regio- and diastereoselectivity observed uses commercially available [Cr(Salen)Cl] as a Lewis acid
catalyst and in combination with a very simple experimental procedure renders the present reaction a facile and practical tool for the synthesis
of chiral nonracemic anti-â-amino alcohols.
Chiral â-amino alcohol units are found in many biologically
contrast, only two reports on the direct catalytic asymmetric
synthesis of anti-â-amino alcohols have been published.4
Both methods are based on the catalytic Mannich-type
reaction and show excellent enantioselectivity. However, the
particular nucleophiles used and the moderate diastereo-
selectivity observed, in some cases, impose some limitations
on their synthetic utility.
active compounds and chiral auxiliaries/ligands that are used
1
in asymmetric synthesis. Several powerful methods exist
for their catalytic enantioselective syntheses, the foremost
of which are the Sharpless’ osmium-catalyzed amino-
2
hydroxylation (AA) of olefins and the direct addition of
3
R-hydroxy ketones to imines (Mannich-type reaction).
Currently these methods provide the most useful entry to
highly enantioenriched syn-amino alcohols. By way of
A direct and practical approach to â-amino alcohols is the
ring opening of 1,2-disubstituted epoxides using amines as
5
the nucleophile. Considering that this type of reaction is
(1) For reviews on the asymmetric synthesis and use of vicinal amino
usually anti-stereospecific, a regio- and enantioselective
aminolysis of trans-epoxides would constitute a useful
alcohols, see: (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (b) Ager,
D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. (c) Kolb, H.
C.; Sharpless, K. B. In Transition Metals for Organic Synthesis; Beller,
M., Bolm, C. Eds.; Wiley-VCH: Weinheim, 1998; p 243.
(
2) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Review: O’Brien, P. Angew. Chem., Int. Ed. 1999,
8, 326.
3) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) C o´ rdova, A.;
(4) (a) Kobayashi, S.; Hishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998,
120, 431. (b) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 4712.
(5) For examples about regioselective aminolysis of 1,2-disubstituted
epoxides, see: (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
1557. (b) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. J. Org. Chem.
1994, 59, 4131.
3
(
Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem.
Soc. 2002, 124, 1842. (c) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc.
003, 125, 338.
2
1
0.1021/ol049372t CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/22/2004

method for the catalytic asymmetric preparation of anti-â-
amino alcohols with complete control of diastereoselectivity
Table 1. Asymmetric Aminolysis of trans-Stilbene Oxide 2
with Anilines Catalyzed by [Cr(Salen)Cl] Complex 1
(Scheme 1). Notwithstanding this, no reports employing this
a,b
Scheme 1. Asymmetric Aminolysis of trans-1,2-Disubstituted
Epoxides Providing anti-â-Amino Alcohols
yield
(%)d
ee of 4
(%)e
ee of 2
(%)f
c
sg
entry
3
T (°C)
t (h)
1
2
a
a
a
a
b
b
c
c
rt
-10
-10
0
rt
0
18
36
36
36
18
24
12
24
91
54
47
92
89
60
98
93
86
97
>99
93
88
93
80
42
30
55
80
28
93
268
47
33
37
3h
4h,i
strategy have appeared in the literature, probably as a
consequence of difficulties in regiocontrol.6
,7
5h
Herein, we present the first highly regio-, diastereo-, and
enantioselective aminolysis of racemic trans-1,2-disubstituted
aromatic epoxides with anilines catalyzed by the com-
mercially available [Cr(Salen)Cl] complex 1. The method
provides facile and practical access to chiral nonracemic anti-
â-amino alcohols. The methodology is also effective for the
desymmetrization of meso-epoxides to obtain highly enan-
tioenriched syn-â-amino alcohols.
6h,i
7h
rt
-10
83
94
81
26
57
8h,i
a
Experimental conditions (0.2 mmol scale): reactions run in 2 M CH2Cl2
under argon atmosphere using a 2:1 ratio of 2 to 3 and 5 mol % of catalyst
b
1
relative to racemic epoxide. The complete anti-selectivity was determined
1
c
d
by H NMR analysis on the crude mixture. rt ) room temperature. Yield
of isolated product based on anilines 3. e The ee values were determined
f
by HPLC on a Chiralpak AD-H column. The unreacted (R,R)-(+)-2 was
completely recovered after chromatography. Selectivity factor; see ref 11
for details. Performed under aerobic atmosphere in undistilled CH2Cl2.
.5 equiv of 2 was used.
g
h
i
2
tivity (97% ee, entry 2). The reaction can also be performed
under more user-friendly conditions by mixing the air-stable
catalyst 1 and the reagents in undistilled CH Cl , without
2 2
any precautions to exclude moisture. Under these conditions
a slight decrease in catalytic activity is observed, but the
amino alcohol 4a is generated in enantiomerically pure form
Considering the high selectivities observed in different
asymmetric ring-opening reactions catalyzed by [Cr(Salen)-
Cl] complex 1, we initially tested the reaction of racemic
trans-stilbene oxide 2 (2 equiv) with aniline 3a (1 equiv)
2 2
using catalyst 1 (0.1 equiv) in CH Cl (Table 1). The reaction
(
s ) selectivity factor ) 268, ee > 99%, entry 3).11 The
8
optimal balance between reactivity and selectivity is achieved
by carrying out the reaction at 0 °C in the open air using an
excess of 2 (2.5 equiv, entry 4).
Another crucial requirement for a simple and synthetically
useful preparation of chiral anti-â-amino alcohols is the use
of an easily removable N-protecting group. Indeed, the use
of p- and o-anisidine 3b and 3c provides the corresponding
N-aryl amino alcohols 4b and 4c, respectively, which can
be efficiently deprotected by oxidative dearylation without
proceeded smoothly at room temperature, providing a high
yield of the desired amino alcohol adduct 4a with complete
9
anti-selectivity and good enantiocontrol (86% ee, entry 1).
Generally, the stereoselectivity of the kinetic resolution
10
displays a strong temperature dependence. Performing the
reaction at -10 °C affords 4a with excellent enantioselec-
12
erosion of stereochemical integrity. Although 3b displayed
a selectivity higher than that of 3c in the room-temperature
reaction (s ) 33 to 26, respectively, entries 5 and 7), the
high reactivity of o-anisidine 3c allowed the aminolysis of
trans-stilbene oxide 2 to be run at -10 °C. Under these
conditions, the anti-â-amino alcohol 4c was isolated in very
high yield and enantioselectivity (entry 8).
(6) Moderate enantioselective ring opening with anilines has been
reported only with meso-epoxides; see: (a) Hou, X.-L.; Wu, J.; Dai, L.-X.;
Xia, L.-J.; Tang, M.-H. Tetrahedron: Asymmetry 1998, 9, 1747. (b) Sekar,
G.; Kamble, R. M.; Singh, V. K. Tetrahedron: Asymmetry 1999, 10, 3663.
(7) Highly enantioselective ring opening with azide has been reported
only with meso- and terminal epoxides. meso-Epoxides, see: (a) Martinez,
L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc.
1
995, 117, 5897. (b) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768.
Terminal epoxides, see: (c) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 1996, 118, 7420. Review: (d) Jacobsen, E. N.; Wu, M.
H. In ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Chapter 35.
The scope of the present asymmetric aminolytic kinetic
resolution (AKR) was demonstrated by the reaction of
(
8) (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
(11) The selectivity factors s were calculated using the equation s )
ln[1 - c(1 + ee)]/ln[1 - c(1 - ee)], where ee is the enantiomeric excess
of the amino alcohol product and c is the conversion; see Supporting
Information for details.
(12) (a) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131. (b)
Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765.
Angew. Chem., Int. Ed. 2004, 43, 84. For a review, see: (b) Jacobsen, E.
N. Acc. Chem. Res. 2000, 33, 421. See also refs 7a and 7c.
(
9) The use of different chiral catalysts (e.g., Co(III)-(Salen) complexes)
and aliphatic amines (e.g., pyrrolidine) resulted in no reaction.
10) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001,
43, 5.
(
3
2174
Org. Lett., Vol. 6, No. 13, 2004

Table 2. Aminolytic Kinetic Resolution (AKR) of Aromatic trans-Epoxidesa,b
a
Experimental conditions (0.2 mmol scale): open-air reactions run in undistilled CH2Cl2 (2 M) using a 2.5:1 ratio of 5 to 3b and 4 mol % of catalyst 1
b
1
relative to racemic epoxides. The complete regio- and anti-diastereoselectivity was determined by H NMR analysis on the crude mixture; PMP ) p-methoxy
phenyl, OMP ) o-methoxy phenyl. Yield of isolated product based on 3b. d The ee values were determined by HPLC on Chiralpak AD-H or AS-H
c
columns. The unreacted epoxides were completely recovered after chromatography. Selectivity factor; see ref 11 for details. g Performed with o-anisidine
e
f
3
c to give product 1-(2-methoxy-phenylamino)-1,2-diphenyl-propan-2-ol 6hc.
various aromatic epoxides (5a-h) with p-anisidine 3b; the
results are reported in Table 2. Although regiocontrol is
generally difficult to achieve in the ring opening of 1,2-
disubstituted oxiranes, the asymmetric aminolysis of aromatic
epoxides with anilines catalyzed by 1 proceeds with complete
regioselectivity for the benzylic carbon.13 Racemic trans-
particular, the tolerance of Lewis basic functionality such
as a phosphonate group allowed the AKR of epoxide 5d to
obtain optically active anti-γ-amino-â-hydroxy phosphonate
6d in high yield and good enantioselectivity (entry 4). Such
molecules are of interest as potential phosphate mimics that
16
are resistant to phosphatase hydrolysis. Noteworthy also
1
,2-disubstituted aromatic epoxides 5a-h with different
was the reaction of 1,2,2′-trisubstituted epoxide 5h, which
allowed a quaternary and a secondary carbon stereocenter
to be set with complete anti-selectivity and good enantio-
meric excess, although with a low reaction rate (entry 8).
The use of o-anisidine 3c ensured completion of the reaction
after 72 h with a slight erosion of the enantioselectivity (entry
9).
substituents in the 2-position or with a fluorine on the
aromatic ring (entry 7), all undergo asymmetric aminolysis
smoothly providing anti-amino alcohols 6 with complete
regio- and diastereoselectivity and in good ee (up to 86%).
The presence of coordinating functional groups does not
appear to affect the catalytic activity of the system. In
14
15
The [Cr(Salen)Cl]-catalyzed asymmetric aminolysis was
also effective for the desymmetrization of meso-stilbene
oxide 7 with anilines 3a-c, which afforded the corresponding
syn-amino alcohols 8 with complete diastereocontrol and high
enantioselectivity (Table 3). Interestingly, the use of a
3
catalytic amount of Et N as additive dramatically increased
(
13) It has been shown that an aromatic substituent on the oxirane ring
usually promotes the ring opening on the adjacent carbon: Jaime, C.; Ortu n˜ o,
R. M.; Font, J. J. Org. Chem. 1988, 53, 139. For a similar regioselectivity
in [Cr(Salen)Cl]-catalyzed kinetic resolution of 1,2-disubstituted aromatic
epoxides, see ref 8a.
17
(14) In all cases, only the anti-diastereomer and a single regioisomer
was detected by NMR and HPLC analysis. The relative stereochemistry
was established through NOE studies on the corresponding cyclic carbam-
ates; see Supporting Information for details.
(16) Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379 and
references therein.
(15) The absolute configuration of 4b was established after conversion
in the corresponding cyclic carbamate and subsequent CAN-promoted
dearylation and by comparison of the optical rotation with an authentic
sample. For products 6 the absolute configuration was assigned by analogy;
see Supporting Information for details.
(17) The AKR of cis-1,2-disubstituted aromatic epoxides (i.e., naphtha-
lene oxide and cis-â-methyl-styrene oxide) afforded the syn-â-amino
alcohols with complete regio- and diastereocontrol but in low enantiomeric
excess (less than 40% ee).
Org. Lett., Vol. 6, No. 13, 2004
2175

asymmetric catalysis. A positive nonlinear effect [(+)-NLE]
was found for the asymmetric aminolysis of meso-stilbene
Table 3. Asymmetric Aminolysis of meso-Stilbene Oxidea,b
18
oxide 7 with aniline 3a; these results suggest that, probably,
more than one molecule of the [Cr(Salen)Cl] catalyst 1 is
involved in the transition state of the enantiodifferentiating
1
9
step. Further studies to elucidate the reaction mechanism
and to expand the scope of the asymmetric AKR of epoxides
are ongoing in our laboratories.
yield (%)c
ee (%)d
entry
3
additive
t (h)
1
2
3
4
a
a
b
c
none
20
40
40
36
95
98
82
91
76
90f
82
80
In summary, we have developed the first highly regio-,
diastereo-, and enantioselective aminolysis of trans-1,2-
disubstituted aromatic epoxides affording anti-â-amino al-
cohols (yield up to 98%, dr > 99/1, ee up to > 99%). The
observed complete anti-selectivity, the commercial avail-
ability of the catalyst 1, and the use of a removable
N-protecting group in combination with a very simple
procedure render the present reaction a facile and practical
tool for the synthesis of enantioenriched anti-â-amino
alcohols.
Et3Ne
Et3Ne
Et3Ne
a
Experimental conditions (0.2 mmol scale): open-air reactions run at rt
in undistilled CH2Cl2 (3 M) using a 1.2:1 ratio of 3 to 7 and 10 mol % of
b
1
catalyst 1. The complete syn-selectivity was determined by H NMR
c
d
analysis on the crude mixture. Yield of isolated product. The ee values
e
were determined by HPLC on Chiralpak AD-H or AS-H columns. 11 mol
%
of Et3N was added. f The (S,S) absolute configuration was established
by comparison of the optical rotation with an authentic sample; see
Supporting Information for details.
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni” supported by MIUR, Rome,
and FIRB National Project “Progettazione, preparazione e
valutazione farmacologica di nuove molecole organiche quali
potenziali farmaci innovativi”.
the enantioselectivity (from 76% to 90% ee, entries 1 and
2) but caused a moderate loss of reactivity.
Probing catalyst systems for a nonlinear relationship
between product enantioselectivity and catalyst enantiopurity
is now commonly being used as a mechanistic tool in
Supporting Information Available: Experimental pro-
cedures and spectral data for all new amino alcohol
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
18) Plot of catalyst ee vs product ee is provided in Supporting
Information.
(19) For similar observations about NLE in other [Cr(Salen)Cl]-catalyzed
asymmetric ring opening of epoxides, see: (a) Hansen, K. B.; Leighton, J.
L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924. For an excellent
review about nonlinear effects, see: (b) Girard, C.; Kagan, H. B. Angew.
Chem., Int. Ed. 1998, 37, 2922.
OL049372T
2176
Org. Lett., Vol. 6, No. 13, 2004